A number of percutaneous intravascular procedures have been developed for treating stenotic atherosclerotic regions of a patient's vasculature to restore adequate blood flow. A common treatment is angioplasty, also known as percutaneous transluminal angioplasty (PTA). PTA is a non-surgical procedure that involves threading a flexible shaft into an artery and briefly inflating a balloon catheter that stretches the blood vessel open and squeezes away the obstruction. PTA, however, is only a partial solution in treating vascular diseases. Further, PTA and other known procedures for opening stenotic regions are associated with formation of plaque in blood vessels and frequent occurrences of restenosis, a re-closing of arteries as a result of injury to the arterial wall during the angioplasty procedure that can necessitate repeat angioplasty procedures or bypass surgery. Long-term restenosis can cause symptoms such as chest pain and fatigue, and increases the danger of heart attack, stroke, and kidney failure, while exposing patients to continued risks of thrombogenesis (blood clotting) and atherosclerosis (hardening of the arteries). It can also lead to recoil, i.e., the mechanical collapse of dilated vessel segment in response to vascular injury.
Restenosis is believed to be caused by smooth muscle cell proliferation or neointimal proliferation known as “hyperplasia” in the vessel wall, a repair response of the body prompted by the arterial trauma resulting from angioplasty. This hyperplasia of smooth muscle cells narrows the lumen opened by angioplasty. Restenosis is also believed to be caused by elastic recoil, the contraction of the vessel wall to its previous position after having been stretched by balloon angioplasty, and by vessel wall remodeling, the formation of scar tissue in the region traumatized by balloon angioplasty. Treatment of restenosis has therefore focused on inhibiting hyperplasia of smooth muscle cells and vessel wall remodeling, and on preventing recoil closure of arteries with an implant.
To inhibit hyperplasia of smooth muscle cells, intravascular radiotherapy has been used. Radiation is commonly used to treat catastrophic diseases such as cancer because of its effectiveness in reducing hyperproliferation of cancerous cells. Localized radiation inhibits cellular proliferation, including smooth muscle proliferation, and has been shown to inhibit, the typical wound healing process. It is believed that radiation breaks down genetic material in the vascular endothelium, causing cell death (apoptosis) and preventing cellular division. A dose-dependent hyperplastic response and a marked reduction in smooth muscle cell build-up have been observed with intravascular radiotherapy.
Thus, attempts have been made to deliver radiation doses with a radioactive implant, such as a radioactive stent. In a radioactive stent, activated radioisotopes are typically either placed inside the stent, alloyed into the metal from which the stent is made, or coated onto the exterior surface of the stent. A radioactive stent is advantageous in that it can obviate the disadvantages associated with catheter-based brachytherapy, such as prolonged insertion of a large intracoronary catheter, which can induce ischemia, and administration of a high dose of a radioactive source to the deep vessel wall, which increases the risk of overexposure to radiation for both patients and physicians. Because the radioactive source is located on the device itself and is implanted right at the site of the lesion, a radioactive stent reduces the risk of inadequate positioning or coverage.
Common sources of radiation used on radioactive stents include pure beta emitting radioisotopes such as phosphorus-32 and yttrium-90. A fundamental problem with pure beta emitting radioactive sources, however, is that radioactivity cannot be precisely calibrated in the microcurie range in a typical catheterization laboratory setting using a conventional well counter as a dose calibrator. Further, uniform in-situ implantation, such as sputter coating, plating or ion deposition of phosphorus-32, which has a 14.3-day half-life, on a stainless steel surface, is complex and problematic. Ion deposition or implantation of stable isotope is a line-of-sight process, and, as a result, the radioactive coating and the isodose/radiation field it produces may not be uniform on the outer circumference, resulting in considerable variation in the radiation dose emitted and delivered to tissue. Moreover, common beta emitters have excessively long ranges of radiation, delivering 95% of the radiation dose within 4 mm of the stent, far more than 100 to 250 micrometers, measured from the intimal layer edge inward towards the external edge of the coronary artery, usually needed to inhibit proliferation of inflammatory cells in coronary arteries. Such excessive irradiation is undesirable and results in unwanted effects, such as weakening of arterial walls and cellular damage.
For example, U.S. Pat. No. 6,187,037 discloses a metal stent for vascular implantation comprising a generally tubular structure whose external surface is adapted to engage the interior vascular surface when implanted, with the metal of the stent containing a substantially uniform dispersion of from about 0.05 to about 10 percent by weight of one or more naturally occurring or enriched stable isotopes having a half-life of less than two months and that are principally beta particle emitters, so that when activated, the stent emits low to moderate dosages of radiation uniformly to reduce cell proliferation.
As an alternative to beta emitting radioisotopes, radioactive tin (Sn-117m, also referred to as tin-117m or 117mSn) has been contemplated because of its short range of emission, which reaches about 0.2 to 0.3 mm in tissue, and the monoenergetic nature of its conversion electron emission. Plating radioactive tin on a metal implant, however, has required a complex process with pronounced drawbacks imposed by tin's radioactivity and a high chloride concentration in the plating solution that is required to dissolve the tin. Because of the specific activity (the number of decays per second per amount of substance) of Sn-117m, which typically ranges between 250 to 5000 mCi per mg (with no carrier added) from accelerator production, to about 2 to 25 mCi per mg of stable tin-117/118 from reactor production, a tin plating solution cannot practically contain more than 10−4 to 10−2 M 117Sn2+, which is several orders of magnitude than the optimal tin plating concentration required in a conventional tin plating process. In addition, to dissolve radioactive tin, the plating solution must maintain a high concentration of chloride, e.g., in the form of tin tetrachloride dissolved in hydrochloric acid, at a level of about 10−1M, in contrast to the chloride concentration used in a plating solution for regular, non-radioactive tin, which is generally kept below 100 ppm. It would be advantageous to provide a process that facilitates radioactive tin plating.
U.S. Pat. No. 6,638,205 discloses a radioactive medical device comprising a radioactive, electroplated substrate coated with at least one layer of polymer and sealed in a jacket layer. The one or more layers of polymer and jacket are provided to reduce leaching of a radioactive element from the electroplated substrate. The radioactive medical device is useful for radiation therapy of diseased tissue such as cancers and especially malignant tumors. P-32, S-35, Cl-36, Sc-47, Cu-67, Y-90, Mo-99, Pd-103, Sn-117m, I-123, I-124, I-125, I-129, I-131, Ce-144, Ho-166, Re-186, Re-188, W-188, Ir-192, and Au-199 are stated as being possible radioactive isotopes while the amount of radioactivity that is provided by such devices in is the range of about 100 to 200 mCi/mm2. The use of the outer layers suggests concern over the quality of adherence of the radioactive isotope to the device. Again, a process that facilitates deposition of radioactive tin coatings is needed.
Thus, there is a need to address the shortcomings of current intravascular radiotherapy technology, including inconsistent dose administration, excessive irradiation of beta emitter therapy, and various procedural shortcomings in designing and preparing implants to deliver radiation to a subject. The present invention now overcomes these shortcomings.